It is now over 70 years since influenza caused the greatest pandemic in modern history resulting in approximately 20 million fatalities, a number that exceeded all those killed in the First World War or in any subsequent man-made or natural disasters. The world is overdue for a new pandemic of influenza. What can be done to prevent or control such an event? Today's technology does not permit production and distribution of vaccine on a scale capable of doing more than blunting the impact of influenza in very few regions of the world. A more realistic approach would be to prevent the appearance of a pandemic influenza virus. There is an ever increasing body of evidence that the new pandemic strains of influenza originate by genetic reassortment between viruses in aquatic birds and those in humans. There is also evidence that this reassortment takes place in domestic pigs in Southeast Asia; probably in The People's Republic of China. The long-term goal of the proposed research is to understand the epidemiological events that result in the origin of pandemics of human influenza in China. Utilizing knowledge gained in the current granting period that the polymerase gene (PBI) present in the human pandemic strains of "Asia-1957" and "Hong Kong-1968" came from different avian sources, we propose the following specific aims: 1. To determine which avian reservoirs are the source of influenza genes in human pandemics. 2. To examine the hypothesis that pigs are the "mixing vessels" of influenza virus genes. and 3. To establish if there is evidence for persistence of earlier human influenza virus in nature. The prevalence of influenza viruses from pigs that contain avian and/or human genes will be established by sequence analysis of the genes and antigenic analysis of the gene products. The geographical distribution of influenza viruses with mixed genomes will be established in virus lineages unique to the "old' and "new' world and in the north and south of China. Of great importance will be determining how often influenza outbreaks in high risk areas of China are associated with the transmission of avian and swine influenza virus genes into human strains. By better understanding the epidemiology of influenza, we may be able to specifically alter agricultural practices which allow the genetic interaction of animal and human influenza viruses and prevent the appearance of a human pandemic.